The prognosis for patients who present with advanced cancers of the pancreas, colon, lung, breast, ovary, brain or prostate is dismal. This tragic situation has stimulated an avalanche of research, resulting in a revolution in understanding cancer pathogenesis, significant gains in the applications of conventional chemotherapeutic agents, and some promising new agents. Unfortunately, this revolution has not yet had a major impact on the treatment of common solid tumors. Many believe that the best hope for future therapeutic gains lies in combining novel approaches with more conventional agents. Our laboratory has been attempting to determine whether spores of C. novyi-NT, a strain of anaerobic bacteria, can be used in such a fashion.
The rationale for using anaerobic bacteria lies in the unique angiogenic state that exists within tumors. It is widely recognized that solid tumors require angiogenesis to grow to a clinically important size (Folkman, 2002; Kerbel, 2000). It is less often appreciated that solid tumors almost always outpace angiogenesis, often resulting in large regions that are poorly vascularized (Brown, 2002). These poorly perfused regions pose major problems for the oncologist. Drug delivery is compromised and drug efficacy suffers not only from the lower drug concentrations reached in avascular areas but also from the fact that many chemotherapeutic agents rely both on oxygen and on actively replicating tumor cells for full potency (Brown and Giaccia, 1998).
The potential of anaerobic bacteria for treating cancer was recognized a half century ago (Jain and Forbes, 2001). Though initial clinical trials of such organisms were discouraging, this approach has more recently been revisited using genetic engineering techniques not available in the past (Heppner and Mose, 1978). For example, a strain of the facultative anaerobe S. typhi was created in which the major endotoxin component was mutated, resulting in a substantial diminution of toxicity (Low et al., 1999). Similarly, a cytosine deaminase gene was introduced into the anaerobe Clostridium sporogenes, endowing these bacteria with potent anti-tumor effects when used in combination with fluorocytosine, a prodrug activated by the introduced gene (Lru et al., 2002). Our group has eliminated the major systemic toxin gene from the strict anaerobe C. novyi, creating a strain called C. novyi-NT that had anti-neoplastic activities when combined with selected chemotherapeutic agents (COBALT, for combination bacteriolytic therapy (Dang et al., 2001).
In a previous study of various chemotherapeutic agents the anti-microtubule agent dolastatin-10, was found to be particularly effective when used in combination with C. novyi-NT spores, though toxicity was problematic (Dang et al., 2001). The mechanistic basis for this efficacy was not known. There is a need in the art for a systematic exploration of the relationship between various anti-microtubule agents and bacteriolytic therapy.